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PDBsum entry 2c4h
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References listed in PDB file
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Key reference
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Title
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Structural insights into substrate traffic and inhibition in acetylcholinesterase.
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Authors
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J.P.Colletier,
D.Fournier,
H.M.Greenblatt,
J.Stojan,
J.L.Sussman,
G.Zaccai,
I.Silman,
M.Weik.
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Ref.
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EMBO J, 2006,
25,
2746-2756.
[DOI no: ]
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PubMed id
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Abstract
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Acetylcholinesterase (AChE) terminates nerve-impulse transmission at cholinergic
synapses by rapid hydrolysis of the neurotransmitter, acetylcholine. Substrate
traffic in AChE involves at least two binding sites, the catalytic and
peripheral anionic sites, which have been suggested to be allosterically related
and involved in substrate inhibition. Here, we present the crystal structures of
Torpedo californica AChE complexed with the substrate acetylthiocholine, the
product thiocholine and a nonhydrolysable substrate analogue. These structures
provide a series of static snapshots of the substrate en route to the active
site and identify, for the first time, binding of substrate and product at both
the peripheral and active sites. Furthermore, they provide structural insight
into substrate inhibition in AChE at two different substrate concentrations. Our
structural data indicate that substrate inhibition at moderate substrate
concentration is due to choline exit being hindered by a substrate molecule
bound at the peripheral site. At the higher concentration, substrate inhibition
arises from prevention of exit of acetate due to binding of two substrate
molecules within the active-site gorge.
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Figure 1.
Figure 1 3D structure of native TcAChE (pdb access code 1EA5),
highlighting the catalytic triad in red, Trp84 in the CAS,
Trp279 at the PAS, and the bottleneck residue Phe330 in blue.
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Figure 8.
Figure 8 Molecular surfaces of the active-site gorge in native
TcAChE (A), and in the OTMA/TcAChE (B), 20 mM TCh/TcAChE (C), 20
mM ATCh/TcAChE (D) and 500 mM ATCh/TcAChE (E) complexes. OTMA,
ATCh and TCh are shown as yellow sticks, as is the acetyl group
on Ser200 in (D, E).
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(2006,
25,
2746-2756)
copyright 2006.
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